Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Classifying BRAF alterations in cancer: new rational therapeutic strategies for actionable mutations

Oncogene volume 37, pages 3183–3199 (2018)Cite this article

Subjects

Abstract

The RAS–RAF–MEK–ERK signaling cascade is among the most frequently mutated pathways in human cancer. Approximately 50% of melanoma patients possess a druggable hotspot V600E/K mutation in the BRAF protein kinase. FDA-approved combination therapies of BRAF and MEK inhibitors are available that provide survival benefits to patients with a BRAF V600 mutation. Non-V600 BRAF mutants are found in many cancers, and are more prevalent than V600 mutations in certain tumor types. For example, between 50–80% of BRAF mutations in non-small cell lung cancer and 22–30% in colorectal cancer encode for non-V600 mutants. As next generation sequencing becomes increasingly used in clinical practice, oncologists are frequently identifying non-V600 BRAF mutations in their patient’s tumors, but are uncertain of viable therapeutic options that could be employed for optimal treatment. From recent studies, a new classification system is emerging for BRAF mutations based on biochemical and signaling mechanisms associated with these mutants. Class I BRAF mutations affect amino acid V600 and signal as RAS-independent active monomers, class II mutations function as RAS-independent activated dimers, and class III mutations are kinase impaired but increase signaling through the MAPK pathway due to enhanced RAS binding and subsequent CRAF activation. These distinct classes of BRAF mutations predict response to targeted therapies and have important implications for future drug development. Herein, we discuss pre-clinical and clinical findings that may lead to improved treatments for all classes of BRAF mutant cancers.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003;3:459–65.

    Article  CAS  PubMed  Google Scholar 

  2. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.

    Article  CAS  PubMed  Google Scholar 

  3. Namba H, Nakashima M, Hayashi T, Hayashida N, Maeda S, Rogounovitch TI, et al. Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. J Clin Endocrinol Metab. 2003;88:4393–7.

    Article  CAS  PubMed  Google Scholar 

  4. Jones JC, Renfro LA, Al-Shamsi HO, Schrock AB, Rankin A, Zhang BY. et al. Non-V600 BRAF mutations define a clinically distinct molecular subtype of metastatic colorectal cancer. J Clin Oncol. 2017;35:2624–30.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Cardarella S, Ogino A, Nishino M, Butaney M, Shen J, Lydon C, et al. Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer. Clin Cancer Res. 2013;19:4532–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Paik PK, Arcila ME, Fara M, Sima CS, Miller VA, Kris MG, et al. Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol. 2011;29:2046–51.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Rapp UR, Goldsborough MD, Mark GE, Bonner TI, Groffen J, Reynolds FH Jr., et al. Structure and biological activity of v-raf, a unique oncogene transduced by a retrovirus. Proc Natl Acad Sci USA. 1983;80:4218–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116:855–67.

    Article  CAS  PubMed  Google Scholar 

  9. Garnett MJ, Rana S, Paterson H, Barford D, Marais R. Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization. Mol Cell. 2005;20:963–9.

    Article  CAS  PubMed  Google Scholar 

  10. Haling JR, Sudhamsu J, Yen I, Sideris S, Sandoval W, Phung W, et al. Structure of the BRAF-MEK complex reveals a kinase activity independent role for BRAF in MAPK signaling. Cancer Cell. 2014;26:402–13.

    Article  CAS  PubMed  Google Scholar 

  11. Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature. 2011;480:387–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Thevakumaran N, Lavoie H, Critton DA, Tebben A, Marinier A, Sicheri F, et al. Crystal structure of a BRAF kinase domain monomer explains basis for allosteric regulation. Nat Struct Mol Biol. 2015;22:37–43.

    Article  CAS  PubMed  Google Scholar 

  13. Roring M, Herr R, Fiala GJ, Heilmann K, Braun S, Eisenhardt AE, et al. Distinct requirement for an intact dimer interface in wild-type, V600E and kinase-dead B-Raf signalling. EMBO J. 2012;31:2629–47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Yao Z, Torres NM, Tao A, Gao Y, Luo L, Li Q, et al. BRAF mutants evade ERK-dependent feedback by different mechanisms that determine their sensitivity to pharmacologic inhibition. Cancer Cell. 2015;28:370–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hu J, Stites EC, Yu H, Germino EA, Meharena HS, Stork PJ, et al. Allosteric activation of functionally asymmetric RAF kinase dimers. Cell. 2013;154:1036–46.

    Article  CAS  PubMed  Google Scholar 

  16. Freeman AK, Ritt DA, Morrison DK. Effects of Raf dimerization and its inhibition on normal and disease-associated Raf signaling. Mol Cell. 2013;49:751–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yao Z, Yaeger R, Rodrik-Outmezguine VS, Tao A, Torres NM, Chang MT, et al. Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS. Nature. 2017;548:234–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Cutler RE Jr, Stephens RM, Saracino MR, Morrison DK. Autoregulation of the Raf-1 serine/threonine kinase. Proc Natl Acad Sci USA. 1998;95:9214–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Beck TW, Huleihel M, Gunnell M, Bonner TI, Rapp UR. The complete coding sequence of the human A-raf-1 oncogene and transforming activity of a human A-raf carrying retrovirus. Nucleic Acids Res. 1987;15:595–609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chuang E, Barnard D, Hettich L, Zhang XF, Avruch J, Marshall MS. Critical binding and regulatory interactions between Ras and Raf occur through a small, stable N-terminal domain of Raf and specific Ras effector residues. Mol Cell Biol. 1994;14:5318–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tran NH, Wu X, Frost JA. B-Raf and Raf-1 are regulated by distinct autoregulatory mechanisms. J Biol Chem. 2005;280:16244–53.

    Article  CAS  PubMed  Google Scholar 

  22. Karoulia Z, Wu Y, Ahmed TA, Xin Q, Bollard J, Krepler C, et al. An integrated model of RAF inhibitor action predicts inhibitor activity against oncogenic BRAF signaling. Cancer Cell. 2016;30:485–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lavoie H, Therrien M. Regulation of RAF protein kinases in ERK signalling. Nat Rev Mol Cell Biol. 2015;16:281–98.

    Article  CAS  PubMed  Google Scholar 

  24. Tran NH, Frost JA. Phosphorylation of Raf-1 by p21-activated kinase 1 and Src regulates Raf-1 autoinhibition. J Biol Chem. 2003;278:11221–6.

    Article  CAS  PubMed  Google Scholar 

  25. Chong H, Guan KL. Regulation of Raf through phosphorylation and N terminus-C terminus interaction. J Biol Chem. 2003;278:36269–76.

    Article  CAS  PubMed  Google Scholar 

  26. Weber CK, Slupsky JR, Kalmes HA, Rapp UR. Active Ras induces heterodimerization of cRaf and BRaf. Cancer Res. 2001;61:3595–8.

    CAS  PubMed  Google Scholar 

  27. Rajakulendran T, Sahmi M, Lefrancois M, Sicheri F, Therrien M. A dimerization-dependent mechanism drives RAF catalytic activation. Nature. 2009;461:542–5.

    Article  CAS  PubMed  Google Scholar 

  28. Kyriakis JM, App H, Zhang XF, Banerjee P, Brautigan DL, Rapp UR, et al. Raf-1 activates MAP kinase-kinase. Nature. 1992;358:417–21.

    Article  CAS  PubMed  Google Scholar 

  29. Dougherty MK, Muller J, Ritt DA, Zhou M, Zhou XZ, Copeland TD, et al. Regulation of Raf-1 by direct feedback phosphorylation. Mol Cell. 2005;17:215–24.

    Article  CAS  PubMed  Google Scholar 

  30. Ritt DA, Monson DM, Specht SI, Morrison DK. Impact of feedback phosphorylation and Raf heterodimerization on normal and mutant B-Raf signaling. Mol Cell Biol. 2010;30:806–19.

    Article  CAS  PubMed  Google Scholar 

  31. Zehir A, Benayed R, Shah RH, Syed A, Middha S, Kim HR, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23:703–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008;26:5705–12.

    Article  PubMed  CAS  Google Scholar 

  33. Tejpar S, Bertagnolli M, Bosman F, Lenz HJ, Garraway L, Waldman F, et al. Prognostic and predictive biomarkers in resected colon cancer: current status and future perspectives for integrating genomics into biomarker discovery. Oncologist. 2010;15:390–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tiacci E, Trifonov V, Schiavoni G, Holmes A, Kern W, Martelli MP, et al. BRAF mutations in hairy-cell leukemia. N Engl J Med. 2011;364:2305–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Preusser M, Bienkowski M, Birner P. BRAF inhibitors in BRAF-V600 mutated primary neuroepithelial brain tumors. Expert Opin Investig Drugs. 2016;25:7–14.

    Article  CAS  PubMed  Google Scholar 

  36. Brastianos PK, Taylor-Weiner A, Manley PE, Jones RT, Dias-Santagata D, Thorner AR, et al. Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas. Nat Genet. 2014;46:161–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Berghoff AS, Preusser M. BRAF alterations in brain tumours: molecular pathology and therapeutic opportunities. Curr Opin Neurol. 2014;27:689–96.

    Article  CAS  PubMed  Google Scholar 

  38. Flaherty KT, McArthur G. BRAF, a target in melanoma: implications for solid tumor drug development. Cancer . 2010;116:4902–13.

    Article  CAS  PubMed  Google Scholar 

  39. Siroy AE, Boland GM, Milton DR, Roszik J, Frankian S, Malke J, et al. Beyond BRAF(V600): clinical mutation panel testing by next-generation sequencing in advanced melanoma. J Invest Dermatol. 2015;135:508–15.

    Article  CAS  PubMed  Google Scholar 

  40. Dahlman KB, Xia J, Hutchinson K, Ng C, Hucks D, Jia P, et al. BRAF(L597) mutations in melanoma are associated with sensitivity to MEK inhibitors. Cancer Discov. 2012;2:791–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. AACR Project GENIE. Powering precision medicine through an international consortium. Cancer Discov. 2017;7:818–31.

    Article  Google Scholar 

  42. Litvak AM, Paik PK, Woo KM, Sima CS, Hellmann MD, Arcila ME, et al. Clinical characteristics and course of 63 patients with BRAF mutant lung cancers. J Thorac Oncol. 2014;9:1669–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511:543–50.

    Article  CAS  Google Scholar 

  44. Noeparast A, Teugels E, Giron P, Verschelden G, De Brakeleer S, Decoster L, et al. Non-V600 BRAF mutations recurrently found in lung cancer predict sensitivity to the combination of Trametinib and Dabrafenib. Oncotarget . 2016;8:60094–108.

    PubMed  PubMed Central  Google Scholar 

  45. Houben R, Becker JC, Kappel A, Terheyden P, Brocker EB, Goetz R, et al. Constitutive activation of the Ras-Raf signaling pathway in metastatic melanoma is associated with poor prognosis. J Carcinog. 2004;3:6.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Santarpia L, Sherman SI, Marabotti A, Clayman GL, El-Naggar AK. Detection and molecular characterization of a novel BRAF activated domain mutation in follicular variant of papillary thyroid carcinoma. Hum Pathol. 2009;40:827–33.

    Article  CAS  PubMed  Google Scholar 

  47. Smalley KS, Xiao M, Villanueva J, Nguyen TK, Flaherty KT, Letrero R, et al. CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations. Oncogene. 2009;28:85–94.

    Article  CAS  PubMed  Google Scholar 

  48. Ikenoue T, Hikiba Y, Kanai F, Tanaka Y, Imamura J, Imamura T, et al. Functional analysis of mutations within the kinase activation segment of B-Raf in human colorectal tumors. Cancer Res. 2003;63:8132–7.

    CAS  PubMed  Google Scholar 

  49. Ikenoue T, Hikiba Y, Kanai F, Aragaki J, Tanaka Y, Imamura J, et al. Different effects of point mutations within the B-Raf glycine-rich loop in colorectal tumors on mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase and nuclear factor kappaB pathway and cellular transformation. Cancer Res. 2004;64:3428–35.

    Article  CAS  PubMed  Google Scholar 

  50. Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140:209–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Foster SA, Whalen DM, Ozen A, Wongchenko MJ, Yin J, Yen I, et al. Activation mechanism of oncogenic deletion mutations in BRAF, EGFR, and HER2. Cancer Cell. 2016;29:477–93.

    Article  CAS  PubMed  Google Scholar 

  52. Johnson DB, Childress MA, Chalmers ZR, Frampton GM, Ali SM, Rubinstein SM, et al. BRAF internal deletions and resistance to BRAF/MEK inhibitor therapy. Pigment Cell Melanoma Res. 2017. https://doi.org/10.1111/pcmr.12674 [Epub ahead of print]

    Article  CAS  Google Scholar 

  53. Chen SH, Zhang Y, Van Horn RD, Yin T, Buchanan S, Yadav V, et al. Oncogenic BRAF deletions that function as homodimers and are sensitive to inhibition by RAF dimer inhibitor LY3009120. Cancer Discov. 2016;6:300–15.

    Article  CAS  PubMed  Google Scholar 

  54. Ross JS, Wang K, Chmielecki J, Gay L, Johnson A, Chudnovsky J, et al. The distribution of BRAF gene fusions in solid tumors and response to targeted therapy. Int J Cancer. 2016;138:881–90.

    Article  CAS  PubMed  Google Scholar 

  55. Jones DT, Hutter B, Jager N, Korshunov A, Kool M, Warnatz HJ, et al. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet. 2013;45:927–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, et al. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 2008;68:8673–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Dankort D, Curley DP, Cartlidge RA, Nelson B, Karnezis AN, Damsky WE Jr., et al. Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nat Genet. 2009;41:544–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. The Cancer Genome Atlas. Genomic classification of cutaneous melanoma. Cell. 2015;161:1681–96.

    Article  CAS  Google Scholar 

  59. Kim DW, Haydu LE, Joon AY, Bassett RL Jr., Siroy AE, Tetzlaff MT, et al. Clinicopathological features and clinical outcomes associated with TP53 and BRAFNon-V600 mutations in cutaneous melanoma patients. Cancer. 2016;123:1372–81.

    Article  PubMed  CAS  Google Scholar 

  60. Dankort D, Filenova E, Collado M, Serrano M, Jones K, McMahon M. A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors. Genes Dev. 2007;21:379–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Andreadi C, Cheung LK, Giblett S, Patel B, Jin H, Mercer K, et al. The intermediate-activity (L597V)BRAF mutant acts as an epistatic modifier of oncogenic RAS by enhancing signaling through the RAF/MEK/ERK pathway. Genes Dev. 2012;26:1945–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Nieto P, Ambrogio C, Esteban-Burgos L, Gomez-Lopez G, Blasco MT, Yao Z, et al. A Braf kinase-inactive mutant induces lung adenocarcinoma. Nature. 2017;548:239–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Okimoto RA, Lin L, Olivas V, Chan E, Markegard E, Rymar A, et al. Preclinical efficacy of a RAF inhibitor that evades paradoxical MAPK pathway activation in protein kinase BRAF-mutant lung cancer. Proc Natl Acad Sci USA. 2016;113:13456–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Marchetti A, Felicioni L, Malatesta S, Grazia Sciarrotta M, Guetti L, Chella A, et al. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol: Off J Am Soc Clin Oncol. 2011;29:3574–9.

    Article  CAS  Google Scholar 

  65. Sakamoto N, Feng Y, Stolfi C, Kurosu Y, Green M, Lin J, et al. BRAFV600E cooperates with CDX2 inactivation to promote serrated colorectal tumorigenesis. eLife. 2017;6:e20331.

  66. Rad R, Cadinanos J, Rad L, Varela I, Strong A, Kriegl L, et al. A genetic progression model of Braf(V600E)-induced intestinal tumorigenesis reveals targets for therapeutic intervention. Cancer Cell. 2013;24:15–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Roth AD, Tejpar S, Delorenzi M, Yan P, Fiocca R, Klingbiel D, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol. 2010;28:466–74.

    Article  CAS  PubMed  Google Scholar 

  68. Van Cutsem E, Lenz HJ, Kohne CH, Heinemann V, Tejpar S, Melezinek I, et al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015;33:692–700.

    Article  CAS  PubMed  Google Scholar 

  69. De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010;11:753–62.

    Article  PubMed  CAS  Google Scholar 

  70. Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369:1023–34.

    Article  CAS  PubMed  Google Scholar 

  71. Shinozaki E, Yoshino T, Yamazaki K, Muro K, Yamaguchi K, Nishina T, et al. Clinical significance of BRAF non-V600E mutations on the therapeutic effects of anti-EGFR monoclonal antibody treatment in patients with pretreated metastatic colorectal cancer: the Biomarker Research for anti-EGFR monoclonal Antibodies by Comprehensive Cancer genomics (BREAC) study. Br J Cancer. 2017;117:1450–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hsu HC, Thiam TK, Lu YJ, Yeh CY, Tsai WS, You JF, et al. Mutations of KRAS/NRAS/BRAF predict cetuximab resistance in metastatic colorectal cancer patients. Oncotarget . 2016;7:22257–70.

    PubMed  PubMed Central  Google Scholar 

  73. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet (Lond, Engl). 2012;380:358–65.

    Article  CAS  Google Scholar 

  74. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Luke JJ, Flaherty KT, Ribas A, Long GV. Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat Rev Clin Oncol. 2017;14:463–82.

    Article  CAS  PubMed  Google Scholar 

  76. Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, Brown MP, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet (Lond, Engl). 2012;379:1893–901.

    Article  CAS  Google Scholar 

  77. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371:1877–88.

    Article  PubMed  CAS  Google Scholar 

  79. Kopetz SDJ, Chan E, Hecht JR, O’Dwyer PJ, Lee RJ, Nolop KB, Saltz L. PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumors. J Clin Oncol. 2010;28:15s.

    Article  CAS  Google Scholar 

  80. Planchard D, Kim TM, Mazieres J, Quoix E, Riely G, Barlesi F, et al. Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17:642–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Falchook GS, Millward M, Hong D, Naing A, Piha-Paul S, Waguespack SG, et al. BRAF inhibitor dabrafenib in patients with metastatic BRAF-mutant thyroid cancer. Thyroid: Off J Am Thyroid Assoc. 2015;25:71–77.

    Article  CAS  Google Scholar 

  82. Kopetz S, Desai J, Chan E, Hecht JR, O’Dwyer PJ, Maru D, et al. Phase II pilot study of vemurafenib in patients with metastatic BRAF-mutated colorectal cancer. J Clin Oncol. 2015;33:4032–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015;373:726–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Lito P, Rosen N, Solit DB. Tumor adaptation and resistance to RAF inhibitors. Nat Med. 2013;19:1401–9.

    Article  CAS  PubMed  Google Scholar 

  85. Solit DB, Garraway LA, Pratilas CA, Sawai A, Getz G, Basso A, et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature. 2006;439:358–62.

    Article  CAS  PubMed  Google Scholar 

  86. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107–14.

    Article  CAS  PubMed  Google Scholar 

  87. Infante JR, Fecher LA, Falchook GS, Nallapareddy S, Gordon MS, Becerra C, et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13:773–81.

    Article  CAS  PubMed  Google Scholar 

  88. Dummer R, Schadendorf D, Ascierto PA, Arance A, Dutriaux C, Di Giacomo AM, et al. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18:435–45.

    Article  CAS  PubMed  Google Scholar 

  89. Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372:30–39.

    Article  PubMed  CAS  Google Scholar 

  90. Larkin J, Ascierto PA, Dreno B, Atkinson V, Liszkay G, Maio M, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371:1867–76.

    Article  PubMed  CAS  Google Scholar 

  91. BioPharma A A Phase Ib/II, Multicenter, Open-label, Dose Escalation Study of LGX818 in Combination With MEK162 in adult patients with BRAF V600-dependent advanced solid tumors. Paper presented at: The Society for Melanoma Research, Thirteenth International Congress, 6–9 November. Boston, MA; 2016.

  92. Planchard D, Besse B, Groen HJ, Souquet PJ, Quoix E, Baik CS, et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol. 2016;17:984–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Corcoran RB, Atreya CE, Falchook GS, Kwak EL, Ryan DP, Bendell JC, et al. Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600-mutant colorectal cancer. J Clin Oncol. 2015;33:4023–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Long GV, Hauschild A, Santinami M, Atkinson V, Mandala M, Chiarion-Sileni V, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377:1813–23.

    Article  CAS  PubMed  Google Scholar 

  95. Yaeger R, Cercek A, O’Reilly EM, Reidy DL, Kemeny N, Wolinsky T, et al. Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients. Clin Cancer Res: Off J Am Assoc Cancer Res. 2015;21:1313–20.

    Article  CAS  Google Scholar 

  96. Huijberts S, Schellens J.H.M, Elez E, Cuyle P, Van Cutsem E, Yaeger R, et al. BEACON CRC: Safety Lead-In (SLI) for the Combination of Binimetinib (BINI), Encorafenib (ENCO), and Cetuximab (CTX) in Patients (Pts) with BRAFV600E Metastatic Colorectal Cancer (mCRC). Ann Oncol. 2017;28 (suppl_5):v158-v208. https://doi.org/10.1093/annonc/mdx393.

  97. Corcoran RB, Ebi H, Turke AB, Coffee EM, Nishino M, Cogdill AP, et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2012;2:227–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Brastianos PK, Shankar GM, Gill CM, Taylor-Weiner A, Nayyar N, Panka DJ, et al. Dramatic response of BRAF V600E mutant papillary craniopharyngioma to targeted therapy. J Natl Cancer Inst. 2015;108(2). djv310..

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Basket study yields approval for rare blood cancer. Cancer Discov. 2018;8(1):4. https://doi.org/10.1158/2159-8290.CD-NB2017-163. Epub 2017 Nov 13..

  100. Brose MS, Cabanillas ME, Cohen EE, Wirth LJ, Riehl T, Yue H, et al. Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17:1272–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Burger MC, Ronellenfitsch MW, Lorenz NI, Wagner M, Voss M, Capper D, et al. Dabrafenib in patients with recurrent, BRAF V600E mutated malignant glioma and leptomeningeal disease. Oncol Rep. 2017;38:3291–6.

    PubMed  PubMed Central  Google Scholar 

  102. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010;464:427–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464:431–5.

    Article  CAS  PubMed  Google Scholar 

  104. Lavoie H, Thevakumaran N, Gavory G, Li JJ, Padeganeh A, Guiral S, et al. Inhibitors that stabilize a closed RAF kinase domain conformation induce dimerization. Nat Chem Biol. 2013;9:428–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012;366:207–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468:973–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Yang H, Higgins B, Kolinsky K, Packman K, Go Z, Iyer R, et al. RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Res. 2010;70:5518–27.

    Article  CAS  PubMed  Google Scholar 

  109. Joshi M, Rice SJ, Liu X, Miller B, Belani CP. Trametinib with or without vemurafenib in BRAF mutated non-small cell lung cancer. PLoS One. 2015;10:e0118210.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Bahadoran P, Allegra M, Le Duff F, Long-Mira E, Hofman P, Giacchero D, et al. Major clinical response to a BRAF inhibitor in a patient with a BRAF L597R-mutated melanoma. J Clin Oncol. 2013;31:e324–326.

    Article  PubMed  Google Scholar 

  111. Posch C, Moslehi H, Feeney L, Green GA, Ebaee A, Feichtenschlager V, et al. Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo. Proc Natl Acad Sci USA. 2013;110:4015–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Hallmeyer S, Gonzalez R, Lawson DH, Cranmer LD, Linette GP, Puzanov I, et al. Vemurafenib treatment for patients with locally advanced, unresectable stage IIIC or metastatic melanoma and activating exon 15 BRAF mutations other than V600E. Melanoma Res. 2017;27:585–90.

    Article  CAS  PubMed  Google Scholar 

  113. Gallo S, Coha V, Caravelli D, Becco P, Venesio T, Zaccagna A, et al. BRAF-inhibitors can exert control of disease in BRAF T599I mutated melanoma: a case report. Melanoma Res. 2017. https://doi.org/10.1097/CMR.0000000000000417. [Epub ahead of print]..

  114. Bowyer SE, Rao AD, Lyle M, Sandhu S, Long GV, McArthur GA, et al. Activity of trametinib in K601E and L597Q BRAF mutation-positive metastatic melanoma. Melanoma Res. 2014;24:504–8.

    Article  CAS  PubMed  Google Scholar 

  115. Marconcini R, Galli L, Antonuzzo A, Bursi S, Roncella C, Fontanini G, et al. Metastatic BRAF K601E-mutated melanoma reaches complete response to MEK inhibitor trametinib administered for over 36 months. Exp Hematol & Oncol. 2017;6:6.

    Article  CAS  Google Scholar 

  116. Richtig G, Aigelsreiter A, Kashofer K, Talakic E, Kupsa R, Schaider H, et al. Two case reports of rare BRAF mutations in exon 11 and exon 15 with discussion of potential treatment options. Case Rep Oncol. 2016;9:543–6.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Haase O, Angun O, Gratz V, Luttmann N, Neumann A, Zillikens D, et al. [Response of BRAF(L597Q)-mutant melanoma to trametinib: Targeted melanoma therapy beyond BRAF(V600) mutations]. Hautarzt. 2016;67:648–52.

    Article  CAS  PubMed  Google Scholar 

  118. Nowroozi S, Zuo Z, Patel K, Patel SP, Luthra R, Routbort M, et al. Clinical characteristics of melanoma patients with non-V600E/K BRAF mutations. J Clin Oncol 2013;31:15_suppl:e20036.

  119. Kim KB, Kefford R, Pavlick AC, Infante JR, Ribas A, Sosman JA, et al. Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol. 2013;31:482–9.

    Article  CAS  PubMed  Google Scholar 

  120. Gautschi O, Peters S, Zoete V, Aebersold-Keller F, Strobel K, Schwizer B, et al. Lung adenocarcinoma with BRAF G469L mutation refractory to vemurafenib. Lung Cancer. 2013;82:365–7.

    Article  PubMed  Google Scholar 

  121. Gautschi O, Milia J, Cabarrou B, Bluthgen MV, Besse B, Smit EF, et al. Targeted therapy for patients with BRAF-mutant lung cancer: results from the European EURAF cohort. J Thorac Oncol. 2015;10:1451–7.

    Article  CAS  PubMed  Google Scholar 

  122. Kulkarni A, Al-Hraishawi H, Simhadri S, Hirshfield KM, Chen S, Pine SR, et al. BRAF fusion as a novel mechanism of acquired resistance to vemurafenib in BRAF V600E mutant melanoma. Clin Cancer Res. 2017;23:5631–8.

    Article  CAS  PubMed  Google Scholar 

  123. Menzies AM, Yeh I, Botton T, Bastian BC, Scolyer RA, Long GV. Clinical activity of the MEK inhibitor trametinib in metastatic melanoma containing BRAF kinase fusion. Pigment Cell Melanoma Res. 2015;28:607–10.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Hutchinson KE, Lipson D, Stephens PJ, Otto G, Lehmann BD, Lyle PL, et al. BRAF fusions define a distinct molecular subset of melanomas with potential sensitivity to MEK inhibition. Clin Cancer Res: Off J Am Assoc Cancer Res. 2013;19:6696–702.

    Article  CAS  Google Scholar 

  125. Sun Y, Alberta JA, Pilarz C, Calligaris D, Chadwick EJ, Ramkissoon SH, et al. A brain-penetrant RAF dimer antagonist for the noncanonical BRAF oncoprotein of pediatric low-grade astrocytomas. Neuro Oncol. 2017;19:774–85.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Kim HS, Jung M, Kang HN, Kim H, Park CW, Kim SM, et al. Oncogenic BRAF fusions in mucosal melanomas activate the MAPK pathway and are sensitive to MEK/PI3K inhibition or MEK/CDK4/6 inhibition. Oncogene. 2017;36:3334–45.

    Article  CAS  PubMed  Google Scholar 

  127. Le K, Blomain ES, Rodeck U, Aplin AE. Selective RAF inhibitor impairs ERK1/2 phosphorylation and growth in mutant NRAS, vemurafenib-resistant melanoma cells. Pigment Cell Melanoma Res. 2013;26:509–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Girotti MR, Lopes F, Preece N, Niculescu-Duvaz D, Zambon A, Davies L, et al. Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma. Cancer Cell. 2015;27:85–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Zhang C, Spevak W, Zhang Y, Burton EA, Ma Y, Habets G, et al. RAF inhibitors that evade paradoxical MAPK pathway activation. Nature. 2015;526:583–6.

    Article  CAS  PubMed  Google Scholar 

  130. Carrera C, Puig-Butille JA, Tell-Marti G, Garcia A, Badenas C, Alos L, et al. Multiple BRAF wild-type melanomas during dabrafenib treatment for metastatic BRAF-mutant melanoma. JAMA Dermatol. 2015;151:544–8.

    Article  PubMed  Google Scholar 

  131. Sereno M, Moreno V, Moreno Rubio J, Gomez-Raposo C, Garcia Sanchez S, Hernandez Jusdado R, et al. A significant response to sorafenib in a woman with advanced lung adenocarcinoma and a BRAF non-V600 mutation. Anti-cancer Drugs. 2015;26:1004–7.

    Article  CAS  PubMed  Google Scholar 

  132. Casadei Gardini A, Chiadini E, Faloppi L, Marisi G, Delmonte A, Scartozzi M, et al. Efficacy of sorafenib in BRAF-mutated non-small-cell lung cancer (NSCLC) and no response in synchronous BRAF wild type-hepatocellular carcinoma: a case report. BMC Cancer. 2016;16:429.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099–109.

    Article  CAS  PubMed  Google Scholar 

  134. Zheng G, Tseng LH, Chen G, Haley L, Illei P, Gocke CD, et al. Clinical detection and categorization of uncommon and concomitant mutations involving BRAF. BMC Cancer. 2015;15:779.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Grilley-Olson JE, Bedard PL, Fasolo A, Cornfeld M, Cartee L, Razak AR, et al. A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K/mTOR inhibitor GSK2126458 in patients with advanced solid tumors. Invest New Drugs. 2016;34:740–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Rose AAN, Biondini M, Curiel R, Siegel PM. Targeting GPNMB with glembatumumab vedotin: current developments and future opportunities for the treatment of cancer. Pharmacol Ther. 2017;179:127–41.

    Article  CAS  PubMed  Google Scholar 

  137. Rose AA, Annis MG, Frederick DT, Biondini M, Dong Z, Kwong L, et al. MAPK pathway inhibitors sensitize BRAF-mutant melanoma to an antibody-drug conjugate targeting GPNMB. Clin Cancer Res. 2016;22:6088–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Rose AANDM, Rajkumar S, Watson IR, Petrecca K, Mihalcioiu C, Siegel PM. Non-V600 BRAF mutations in melanoma: actionable targets for rational drug combinations. Paper presented at: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer. Philadelphia, PA; 2017.

  139. Frederick DT, Piris A, Cogdill AP, Cooper ZA, Lezcano C, Ferrone CR, et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res. 2013;19:1225–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Reddy SM, Reuben A, Wargo JA. Influences of BRAF inhibitors on the immune microenvironment and the rationale for combined molecular and immune targeted therapy. Curr Oncol Rep. 2016;18:42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Miller WH, Kim TM, Lee CB, Flaherty KT, Reddy S, Jamal R, et al. Atezolizumab (A)+cobimetinib (C) in metastatic melanoma (mel): Updated safety and clinical activity. J Clin Oncol. 2017;35(15_suppl):3057.

    Article  Google Scholar 

  142. Bendell JC, Kim TW, Goh BC, Wallin J, Oh D-Y, Han S-W, et al. Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC). J Clin Oncol. 2016;34(15_suppl):3502.

    Article  Google Scholar 

  143. Sullivan RJ, Gonzalez R, Lewis KD, Hamid O, Infante JR, Patel M, et al. Atezolizumab (A)+cobimetinib (C)+vemurafenib (V) in BRAFV600-mutant metastatic melanoma (mel): updated safety and clinical activity. J Clin Oncol. 2017;35(15_suppl):3063.

    Article  Google Scholar 

  144. Garman B, Anastopoulos IN, Krepler C, Brafford P, Sproesser K, Jiang Y, et al. Genetic and genomic characterization of 462 melanoma patient-derived xenografts, tumor biopsies, and cell lines. Cell Rep. 2017;21:1936–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Krepler C, Sproesser K, Brafford P, Beqiri M, Garman B, Xiao M, et al. A comprehensive patient-derived xenograft collection representing the heterogeneity of melanoma. Cell Rep. 2017;21:1953–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank members of the Siegel and Watson laboratories for their critical comments on the manuscript.

Funding

MD acknowledges MD/PhD training support from the Canadian Institutes of Health Research (CIHR) and the Brain Tumor Foundation of Canada. AANR acknowledges receipt of a David Cornfield Melanoma Fund Award. PMS acknowledges research support from the US Department of Defense (US DOD - CA140389), IRW is funded by grants from the Melanoma Research Alliance (MRA – Grant #412429), the V Foundation (Grant #V2016–023), and the Canadian Institute of Health Research (CIHR – Grant # PJT-152975). PMS is a William Dawson Scholar of McGill University and IRW is a Canada Research Chair.

Author information

Author notes

    Authors and Affiliations

    1. Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada

      Matthew Dankner, Shivshankari Rajkumar, Peter M. Siegel & Ian R. Watson

    2. Department of Medicine, McGill University, Montreal, QC, Canada

      Matthew Dankner & Peter M. Siegel

    3. Department of Medicine, Division of Medical Oncology, University of Toronto, Toronto, ON, Canada

      April A. N. Rose

    4. Department of Biochemistry, McGill University, Montreal, QC, Canada

      Shivshankari Rajkumar & Ian R. Watson

    Authors
    1. Matthew Dankner
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. April A. N. Rose
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Shivshankari Rajkumar
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Peter M. Siegel
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Ian R. Watson
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Ian R. Watson.

    Ethics declarations

    Conflict of interest

    The authors declare that they have no conflict of interest.

    Additional information

    These authors contributed equally: Matthew Dankner and April A.N. Rose.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Dankner, M., Rose, A.A.N., Rajkumar, S. et al. Classifying BRAF alterations in cancer: new rational therapeutic strategies for actionable mutations. Oncogene 37, 3183–3199 (2018). https://doi.org/10.1038/s41388-018-0171-x

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1038/s41388-018-0171-x

    This article is cited by

    Search

    Advanced search

    Quick links